Microfluidic systems have been gaining increasing interest for use in chemical and biochemical analysis and synthesis. Miniaturization of a variety of laboratory analyses provides myriad benefits, including providing substantial savings in time of analysis, cost of analysis, and space requirements for the equipment which performs this analysis. Another touted advantage of microfluidic systems is their suggested adaptability as automated systems, thereby providing additional savings associated with the costs of the human factor of performing analyses, e.g., labor costs, costs associated with operator error, and generalized costs associated with the imperfection of human operations, generally.
A number of different microfluidic technologies have been proposed for realizing the potential of these systems. For example, microfluidic systems have been proposed that are based upon microscale channels or conduits through which fluid is transported by internal or external pressure sources, e.g., pressure pumps, and wherein fluid direction, e.g., as between two potential fluid paths, is carried out using microfabricated mechanical valve structures. Other unrealized technologies have proposed utilizing acoustic energy, or electrohydrodynamic pumping of fluids to effect fluid movement. However, due to fundamental problems with these technologies, e.g., excessive costs or inoperability, they have largely floundered in the research institutions where they were originally conceived.
Electrokinetic material transport systems have shown the ability to fulfill the promise of microfluidics by providing an accurate, automatable, easily manufacturable system for manipulating fluids within microscale systems. Despite the advances of electrokinetic flow systems, it would generally be desirable to provide more and more complex systems for performing a wide variety of different fluidic operations, integrating multiple operations in a single microfluidic system, as well as provide systems capable of performing massively parallel experimentation. In order to provide such systems, it would generally be desirable to provide such systems with advanced abilities to monitor and control the relevant parameters of any and all fluidic elements within a given system, including variables such as temperature, time of reaction, length of separations, and the like. The present invention provides methods and systems that meet these and other needs by providing an operator with greater ability to monitor and control microfluidic systems.
The present invention is generally directed to methods and systems utilized in monitoring and controlling flow rates within microfluidic channel systems. As such, in a first aspect, the present invention provides a method of monitoring an electroosmotic flow rate of fluid in a microfluidic device having at least first and second intersecting microscale-channels disposed therein. The method comprises flowing a fluid along the first channel by applying a voltage gradient across a length of the first channel. A detectable amount of a signaling compound is then injected into the first channel. The flow rate of fluid in the first channel is then determined from the rate at which the signaling compound flows from a first point in the first channel to a second point in the first channel. This is repeated in a second channel. Specifically, a fluid is also flowed along the second channel by applying a voltage gradient across a length of the second channel, a detectable amount of a signaling compound is injected into the second channel, and the flow rate of fluid in the second channel is determined from the rate at which the signaling compound flows from a first point in the second channel to a second point in the second channel.
In an alternate embodiment, the present invention provides a microfluidic system employing at least first and second intersecting microscale channels disposed in a body structure, wherein the system is used for analyzing a result of a chemical reaction which produces a first detectable signal. In particular, the present invention provides a method of monitoring a flow rate of a fluid in the first channel, which comprises flowing a fluid in the first channel and injecting into the first channel, a detectable amount of a signaling compound. In this aspect, the signaling compound produces a second detectable signal that is capable of being distinguished from the first detectable signal. The second detectable signal is then detected and distinguished from the first detectable signal. The flow rate of fluid in the main channel is then calculated from the amount of time between the injecting step and the detecting step.
In still another aspect, the present invention provides methods of continuously monitoring electroosmotic flow rate of a fluid in a microscale channel of a microfluidic device having at least first and second intersecting microscale channels disposed therein. The method comprises electroosmotically flowing the fluid along the first channel by applying a voltage gradient across the length of the first channel. A detectable amount of a signaling compound is periodically injected into the first channel at a first point. The periodic signal from the signaling compound is then detected at a second point in the first channel, the second point being removed from the first point. Variation in flow rate is then identified from a variation in the periodic signal detected in the detecting step.
In an additional aspect, the present invention provides a microfluidic device for use in accordance with the monitoring methods described herein. In particular, the device comprises a body structure having at least first, second and third channels disposed therein. The first channel comprises first and second reservoirs in fluid communication with its first and second termini. The first reservoir has the fluid deposited therein. The second channel intersects the first channel at a first terminus of the second channel, and has a third reservoir in fluid communication with a second terminus of the second channel. The third reservoir has a signaling compound disposed therein, which signaling compound is capable of producing a detectable signal. The third channel intersects the first channel at a first terminus of the third channel and has a fourth reservoir in fluid communication with a second terminus of the third channel. The device also comprises a detection window disposed across at least one of the first and second microscale channels, wherein the detection window is capable of transmitting the detectable signal therethrough.
The monitoring methods described herein are also useful in methods of controlling the electroosmotic flow rate of a fluid in a microfluidic device having at least a first microscale channel disposed therein. In particular, an electroosmotic flow rate is controlled by a method which comprises flowing the fluid along the first channel by applying a voltage gradient across a length of the first channel. A detectable amount of a signaling compound is injected into the first channel at a first point in the first channel. The actual flow rate of fluid is then determined from the rate at which the signaling compound flows along the first channel. The actual flow rate is then compared to a desired flow rate. The voltage gradient applied across the length of the first channel is then increased or decreased until the actual flow rate is approximately equal to the desired flow rate.
In a related aspect, the present invention provides a system for controlling an electroosmotic flow rate of a fluid in a microfluidic system. The system comprises a microfluidic device comprising at least first, second and third channels disposed therein, the first channel having first and second reservoirs in fluid communication with its first and second termini, the first reservoir having the fluid deposited therein, the second channel intersecting the first channel at a first terminus of the second channel, and having a third reservoir in fluid communication with a second terminus of the second channel the third reservoir having a signaling compound disposed therein, the third channel intersecting the first channel at a first terminus of the third channel, and having a fourth reservoir in fluid communication with a second terminus of the third channel. The system also comprises an electrical controller for concomitantly applying and modulating voltages at at least three of the first, second, third and fourth reservoirs, to flow a fluid in the first channel from the first reservoir to the second reservoir, and periodically injecting a detectable amount of the signaling compound into the first channel from the third reservoir. The system further includes a detector disposed adjacent to and in sensory communication with a point in the first channel, whereby the detector is capable of detecting the signaling compound at the first point in the first channel. In addition, the system comprises an appropriately programmed computer for receiving signal data from the detector, calculating the actual flow rate of the fluid in the channel from the signal data, comparing the actual flow rate, and instructing the electrical controller to increase or decrease the voltage gradient across the channel based upon a difference between the actual flow rate and the desired flow rate.
In still another aspect, the present invention provides a computer or processor for use in accordance with the monitoring and controlling methods and systems described herein. The computer or processor comprises appropriate programming for determining an actual electroosmotic flow rate of a fluid in a first microscale channel. The computer then compares the actual electroosmotic flow rate to a desired electroosmotic flow rate in the first microscale channel, and increases or decreases the voltage gradient applied across the first microscale channel depending upon the comparison of the actual electroosmotic flow rate to the desired electroosmotic flow rate, until the actual electroosmotic flow rate is approximately equal to the desired electroosmotic flow rate.